As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma: the SYGMA2 trial

What's the clinical question?

In patients with mild asthma, is PRN budesonide-formoterol non-inferior to budesonide maintenance therapy in preventing severe asthma exacerbations?

PICO

Study Design

This study was a double-blind, multicenter, parallel-group randomized controlled trial conducted over 52 weeks across 354 sites in 25 countries.

There was a 2 to 4 week run-in period where patients used PRN terbutaline alone for symptom relief, before randomization. Randomization was stratified by study site, and computer generated. During the 52-week period there was no regular medication reminders.

Follow-up over 52 weeks was done through both scheduled in-person visits and phone contact.

How were outcomes assessed?

Primary

• Annualized rate of severe exacerbations - identified during follow-ups. Additional hospitalizations/systemic steroid use during a severe asthma exacerbation were not counted as new events

Secondary

• Spirometry: very detailed criteria for reproducibility are provided in the protocol (ie. timing, model specs, positioning, etc.)
• ACQ-5 and AQLQ: self-administered during in-person follow-up visits
• Puffer Usage (Turbuhaler/placebo): a battery powered electronic data logger used for ‘as needed’ and maintenance investigational product

Statistical analysis

A negative binomial regression model was used for the rate of severe exacerbations, adjusting for treatment group, pretrial treatment, geographic region.

Time to the first severe exacerbation was analyzed using a Cox proportional-hazards model with the same adjustment factors. Changes in ACQ-5/AQLQ scores and FEV1 were analyzed using a mixed model for repeated measures. "No adjustments for multiple comparisons for secondary efficacy variables were made."

Results

Table 1: patients

4215 patients were randomized, with 4176 included in the full analysis set (2089 in the budesonide-formoterol group and 2087 in the budesonide maintenance group). Overall the groups were well balanced, in particular with age, sex, region, and smoking status (mean age 41 years, ~60% female). Asthma characteristics were also well balanced (see below table). Notably, roughly half of the patients had a baseline ACQ-5 score of ≥1.5.

From each group, only about 1% of patients were lost to follow-up.

Primary Outcome

PRN budesonide-formoterol was non-inferior to budesonide maintenance therapy for the annualized rate of severe asthma exacerbations, with rates of 0.11 (95% CI, 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (RR 0.97; upper one-sided 95% confidence limit, 1.16).

Secondary Outcomes

Exacerbations - time to first, total numbers

No significant difference was found between groups for time to first severe exacerbation. There was no significant difference in rate of exacerbations depending on pretrial treatment.

In total, 8.5% of the budesonide-formoterol group compared to 8.8% in the budesonide had a severe exacerbation, a non-significant difference.

ACQ-5, AQLQ

In both groups, the ACQ-5 and AQLQ score trended towards better control; while both analyses were not controlled for multiple comparisons, they both favoured the budesonide maintenance group.

However, the actual magnitude of change for both scores was relatively small:

• ACQ-5: the mean difference between budesonide maintenance and PRN Symbicort scores was 0.11 (95% CI, 0.07 to 0.15); at the end of 52 weeks, 40.3% vs. 44.3% had a decrease of ≥0.5 (OR 0.86; 95% CI, 0.75 to 0.99, p=0.036). If you took that 4% difference at face-value, the NNT to decrease the ACQ-5 score by 52 weeks would be 25
• AQLQ: the mean difference between budesonide maintenance and PRN Symbicort scores was -0.096 (95% CI, -0.137 to -0.054)

Spirometry (FEV1)

• Baseline pre-bronchodilator FEV1 increased in both groups, but moreso the budesonide maintenance group
• Mean difference between groups was −32.6 ml (95% CI, −53.7 to −11.4), though across the 52 weeks the greatest difference was at the first 16 weeks before the groups converged (? effect of increased compliance during first weeks - unclear from the paper if this was queried)

Puffer and steroid use

Adherence to the blinded maintenance regimen was the same between groups: around 60%±30%; there was no data on adherence over time.

• For PRN doses: 0.52 inhalations ± 0.55/day of Symbicort on average, vs 0.49±0.70/day of terbutaline
• Less patients required high PRN puffer use at least once in a day for the Budesonide-Formoterol group: 10% vs 15% for >8 inhalations, 4.1% vs 7.4% for >12 inhalations
• Budesonide-formoterol patients had a 75% lower median daily dose of inhaled glucocorticoid: 66 µg compared to 267 µg. Median days with systemic steroids was 6 days in both groups.

Adverse Events

Adverse events were similar between groups. One asthma-related death in budesonide maintenance group, and one non-asthma death in the budesonide-formoterol group.

Limitations

• Majority of the population was Caucasian
• Adherence rates of 60% are much higher than real life, favouring the maintenance budesonide group
• 52 weeks may not be enough for assessment of long-term outcomes
• No adjustments for multiple comparisons in secondary efficacy analyses, giving less confidence in the ACQ-5/AQLQ results

Risk of Bias 2 for primary outcome

Outcome: low risk